PMID: 20534510

 

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Title : Structures of a platelet-derived growth factor /propeptide complex and a platelet-derived growth factor /receptor complex

Abstract :
  1. Platelet-derived growth factors ( PDGFs ) and their receptors ( PDGFRs ) are prototypic growth factors and receptor tyrosine kinases which have critical functions in development
  2. We show that PDGFs share a conserved region in their prodomain sequences which can remain noncovalently associated with the mature cystine-knot growth factor domain after processing
  3. The structure of the PDGF-A /propeptide complex reveals this conserved, hydrophobic association mode
  4. We also present the structure of the complex between PDGF-B and the first three Ig domains of PDGFRbeta , showing that two PDGF-B protomers clamp PDGFRbeta at their dimerization seam
  5. The PDGF-B : PDGFRbeta interface is predominantly hydrophobic, and PDGFRs and the PDGF propeptides occupy overlapping positions on mature PDGFs , rationalizing the need of propeptides by PDGFs to cover functionally important hydrophobic surfaces during secretion
  6. A large-scale structural organization and rearrangement is observed for PDGF-B upon receptor binding, in which the PDGF-B L1 loop, disordered in the structure of the free form, adopts a highly specific conformation to form hydrophobic interactions with the third Ig domain of PDGFRbeta
  7. Calorimetric data also shows that the membrane-proximal homotypic PDGFRalpha interaction, albeit required for activation, contributes negatively to ligand binding
  8. The structural and biochemical data together offer insights into PDGF- PDGFR signaling, as well as strategies for PDGF-antagonism